Reexamining Alzheimer’s disease: Evidence for a protective role for amyloid-beta protein precursor and amyloid-beta. Journal of Alzheimer’s Disease, 18(2), 447-452

Department of Pathology, University of Maryland, Baltimore, MD 21201, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 08/2009; 18(2):447-52. DOI: 10.3233/JAD-2009-1151
Source: PubMed


Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-beta as the major pathogenic mechanism with the ultimate goal of using amyloid-beta lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies'' and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition.

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Available from: George Perry, Oct 04, 2015
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    • "In understanding the role of Aβ in the pathogenesis of AD, two important questions remain unanswered: 1) what are the triggering mechanisms that primarily induce Aβ deposition? and 2) why does Aβ relentlessly accumulate in such a destructive manner? The first question has not been fully addressed, although some interesting hypotheses have been advanced [116], [117], [154]–[157]. In relation to the second, recent data suggest that Aβ deposits self-propagate through the continuous accretion of misfolded and degradation-resistant molecules [108], [158]. "
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    ABSTRACT: Defining the biochemical alterations that occur in the brain during "normal" aging is an important part of understanding the pathophysiology of neurodegenerative diseases and of distinguishing pathological conditions from aging-associated changes. Three groups were selected based on age and on having no evidence of neurological or significant neurodegenerative disease: 1) young adult individuals, average age 26 years (n = 9); 2) middle-aged subjects, average age 59 years (n = 5); 3) oldest-old individuals, average age 93 years (n = 6). Using ELISA and Western blotting methods, we quantified and compared the levels of several key molecules associated with neurodegenerative disease in the precuneus and posterior cingulate gyrus, two brain regions known to exhibit early imaging alterations during the course of Alzheimer's disease. Our experiments revealed that the bioindicators of emerging brain pathology remained steady or decreased with advancing age. One exception was S100B, which significantly increased with age. Along the process of aging, neurofibrillary tangle deposition increased, even in the absence of amyloid deposition, suggesting the presence of amyloid plaques is not obligatory for their development and that limited tangle density is a part of normal aging. Our study complements a previous assessment of neuropathology in oldest-old subjects, and within the limitations of the small number of individuals involved in the present investigation, it adds valuable information to the molecular and structural heterogeneity observed along the course of aging and dementia. This work underscores the need to examine through direct observation how the processes of amyloid deposition unfold or change prior to the earliest phases of dementia emergence.
    PLoS ONE 08/2014; 9(8):e105784. DOI:10.1371/journal.pone.0105784 · 3.23 Impact Factor
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    • "The amyloid hypothesis has been the predominant theory of AD etiology for the past two decades (Hardy and Selkoe, 2002). Doubts have surfaced concerning whether Aβ is the ultimate cause of AD in humans (Lee et al., 2004; Castellani et al., 2009; Mullane and Williams, 2013; Roher et al., 2013; Tayeb et al., 2013), but recent neuropathological research shows that individuals who have high levels of Aβ postmortem, but do not have soluble forms of Aβ localized to synapses, did not have prior cognitive impairment (Bjorklund et al., 2012). This finding is consistent with the results of studies on non-human animals showing that high Aβ levels cause abnormalities in synaptic plasticity. "
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    ABSTRACT: The leading hypothesis on Alzheimer Disease (AD) is that it is caused by buildup of the peptide amyloid-β (Aβ), which initially causes dysregulation of synaptic plasticity and eventually causes destruction of synapses and neurons. Pharmacological efforts to limit Aβ buildup have proven ineffective, and this raises the twin challenges of understanding the adverse effects of Aβ on synapses and of suggesting pharmacological means to prevent them. The purpose of this paper is to initiate a computational approach to understanding the dysregulation by Aβ of synaptic plasticity and to offer suggestions whereby combinations of various chemical compounds could be arrayed against it. This data-driven approach confronts the complexity of synaptic plasticity by representing findings from the literature in a course-grained manner, and focuses on understanding the aggregate behavior of many molecular interactions. The same set of interactions is modeled by two different computer programs, each written using a different programming modality: one imperative, the other declarative. Both programs compute the same results over an extensive test battery, providing an essential crosscheck. Then the imperative program is used for the computationally intensive purpose of determining the effects on the model of every combination of ten different compounds, while the declarative program is used to analyze model behavior using temporal logic. Together these two model implementations offer new insights into the mechanisms by which Aβ dysregulates synaptic plasticity and suggest many drug combinations that potentially may reduce or prevent it.
    Frontiers in Pharmacology 05/2014; 5:85. DOI:10.3389/fphar.2014.00085 · 3.80 Impact Factor
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    • "Our discussion here focuses on oligomers, but the reader should note that the role fibrils play in AD remains unclear. Are they protective [29]? Are they pathologic [42]? "
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    ABSTRACT: According to Thomas Kuhn, the success of 'normal science,' the science we all practice on a daily basis, depends on the adherence to, and practice of, a paradigm accepted by the scientific community. When great scientific upheavals occur, they involve the rejection of the current paradigm in favor of a new paradigm that better integrates the facts available and better predicts the behavior of a particular scientific system. In the field of Alzheimer's disease, a recent example of such a paradigm shift has been the apparent rejection of the 'amyloid cascade hypothesis,' promulgated by Hardy and Higgins in 1992 to explain the etiology of Alzheimer's disease, in favor of what has been referred to as the 'oligomer cascade hypothesis'. This paradigm shift has been breathtaking in its rapidity, its pervasiveness in the Alzheimer's disease field, and its adoption in an increasing number of other fields, including those of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and the prionoses. However, these facts do not mean, a priori, that the experiments extant, and any re-interpretation of them, should be accepted by rote as support for the new paradigm. In the discussion that follows, I consider the foundational studies leading to the oligomer cascade hypothesis and evaluate the current state of the paradigm. I argue here that, more often than not, insufficient rigor has been applied in studies upon which this new paradigm has been based. Confusion, rather than clarity, has resulted. If the field is to make progress forward using as its paradigmatic basis amyloid β-protein oligomerization, then an epistemological re-evaluation of the amyloid β-protein oligomer system is required.
    Alzheimer's Research and Therapy 08/2013; 5(4):39. DOI:10.1186/alzrt203 · 3.98 Impact Factor
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